TRANSFUSION MEDICINE/HEMOSTASIS CLINICAL RESEARCH NETWORK
Release Date: August 29, 2001
RFA: RFA-HL-02-001 (See RFA-HL-06-108 for Continuation)
National Heart, Lung, and Blood Institute
(http://www.nhlbi.nih.gov/index.htm)
Letter of Intent Receipt Date: January 25, 2002
Application Receipt Date: February 22, 2002
PURPOSE
The National Heart, Lung, and Blood Institute (NHLBI) invites applications to
participate in a Transfusion Medicine/Hemostasis Clinical Research Network
(Network) of interactive clinical research groups. This network will promote
the efficient comparison of novel management strategies of potential benefit
for children and adults with hemostatic disorders such as idiopathic
thrombocytopenia (ITP) and thrombotic thrombocytopenic purpura (TTP) and also
will evaluate novel as well as existing blood products and cytokines for the
treatment of hematologic disorders. The objective of this Request for
Applications (RFA) is to establish and maintain (1) the infrastructure
required for a network of up to sixteen core clinical centers to perform
multiple clinical trials and (2) a Data Coordinating Center for the Network.
The project period for applications submitted in response to this RFA will be
five years. An administrative review will be conducted in approximately the
third year of the network to determine whether or not the network program
should be announced for another five-year funding period. The total project
period for this program will be no longer than 10 years. The anticipated
award date is September 30, 2002.
HEALTHY PEOPLE 2010
The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2010" a PHS-led national
activity for setting priority areas. This RFA, Transfusion Medicine/
Hemostasis Clinical Research Network, is related to one or more of the
priority areas. Potential applicants may obtain a copy of AHealthy People
2010" at http://www.health.gov/healthypeople/.
ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State and local governments, and eligible agencies of
the Federal government. Foreign institutions are not eligible. This
geographic constraint is necessary because of the need for close communication
among members of the program, the requirement for frequent steering committee
meetings, and the necessity of site visits for data verification.
Racial/ethnic minority individuals, women, and persons with disabilities are
encouraged to apply as Principal Investigators.
The disciplines and expertise that will be sought for this program include but
are not limited to the areas of transfusion medicine, pediatrics, internal
medicine, hematology, immunology, pharmacology, therapeutic development,
biostatistics and clinical trials management. Awards for a Core Clinical
Center and a Data Coordinating Center under this RFA will not be made to the
same Principal Investigator to ensure that data analysis is conducted
independently of data acquisition. The same institution may apply for both a
Core Clinical Center and the Data Coordinating Center award, but the
applications for each must be from different individuals. Two or more
separate applications for a Core Clinical Center may be submitted from the
same institution.
MECHANISM OF SUPPORT
This RFA will use the National Institutes of Health (NIH) cooperative
agreement (U01) award mechanism. Under the cooperative agreement, the NIH
assists, supports, and/or stimulates, and is substantially involved with
recipients in conducting a study by facilitating performance of the effort in
a "partner" role. Details of the responsibilities, relationships, and
governance of a study funded under a cooperative agreement are discussed later
in this document.
FUNDS AVAILABLE
The NHLBI intends to commit a maximum of $30 million (total costs) over a
five-year period to this RFA. A Core Clinical Center applicant may request a
project period of up to five years and a budget for total costs of up to
$300,000 per year. This includes up to $150,000 total costs to support core
activities and up to $150,000 total costs for per-patient costs. (Total costs
include Direct costs and Facility & Administrative costs, also called indirect
costs or overhead.) Data Coordinating Center applicants may request a project
period of up to five years and a budget for total costs of up to $850,000 per
year for routine data center functions. In addition to a well documented
budget for data coordinating activities, Data Coordinating Center applicants
should request a line item of additional funds of $280,000 total costs per
year specifically for biologic reagents, centralized laboratory costs and
enrollment of patients from non-Core centers.
A maximum of sixteen awards for Core Clinical Centers and one award for a Data
Coordinating Center will be made under this RFA. Because the nature and scope
of the research proposed in response to this RFA may vary, it is anticipated
that the size of an award may also vary in all years. Funds for patient-
related costs will be restricted and released concordant with patient
enrollment. Future year costs will be distributed based on the recommended
protocols.
Although the financial plan of NHLBI is to provide support for this program,
awards pursuant to this RFA are contingent upon the availability of funds and
the receipt of a sufficient number of meritorious applications. At this time,
it is not known if this RFA will be reissued.
RESEARCH OBJECTIVES
Background
Clinical issues in transfusion medicine/hemostasis are sometimes focused on a
large number of relatively rare diseases. For this reason, it is difficult to
answer clinical questions of note due to the lack of a critical number of
patients at any given institution. The NHLBI Workshop on Development of New
Therapies for Rare Blood Diseases held on July 14, 1999 and a Working Group on
Clinical Research in Transfusion Medicine/Hemostasis that was convened on
August 18, 2000 recommended the facilitation of clinical trials in this area
with increased links to regulatory agencies such that therapeutic development
could be fostered. Functioning clinical networks in Europe have fostered the
collaborative approach to clinical problems and have been relatively
successful. Similar networks for studies in the areas of transfusion
medicine/hemostasis are not available in the U.S.
There is an urgent need to evaluate promising new therapies for hemostatic
disorders such as ITP and TTP and to evaluate new blood products, especially
platelets and platelet substitutes, and cytokines such as thrombopoietin.
Each year, thousands of patients receive platelet transfusions or are treated
for autoimmune hemostatic disorders and yet few have the opportunity to
participate in clinical trials that would potentially result in improved
patient care. There are several reasons why a Transfusion Medicine/Hemostasis
Clinical Research Network would accelerate clinical research and translation
of research to practice. Multi-center trials will reduce the number of
patients needed at each clinical center and allow accrual to be completed more
rapidly. Further, a common treatment protocol will reduce variables that
contribute to patient outcome and allow valid comparisons between treatments.
Finally, the Network approach will increase the number of comparative trials
that are conducted by providing a framework for rapid initiation of important
studies, a focus on randomized studies, and efficient use of pooled clinical
expertise and data management resources.
Organization of the Transfusion Medicine/Hemostasis Clinical Research Network
The Network will be comprised of the Core Clinical Centers, one Data
Coordinating Center, and the NHLBI. Core Clinical Centers will be responsible
for proposing protocols that could be adopted by the Network, guiding protocol
development, enrolling patients, analyzing results, and disseminating research
findings. All Core Clinical Centers will be required to participate in a
cooperative and interactive manner with one another and with the Data
Coordinating Center. A Core Clinical Center has the option to form a
consortium and apply as a single entity for a Core Clinical Center award.
Collaborations within a center are also encouraged (e.g. between investigators
in transfusion medicine and those in hemostasis). In the case of a
consortium, there will be one Principal Investigator who will serve on the
Steering Committee and represent the other centers, and the maximum total
costs per year will be limited to $300,000.
A centralized Data Coordinating Center will support the activities of the
Network. These include devising novel comparative study designs, providing
sample size calculations and statistical advice, developing data forms,
performing data analyses, coordinating the activities of the Steering
Committee, Protocol Review Committee, and Data and Safety Monitoring Board,
and overall study coordination and quality assurance. In addition, in order
to hasten accrual in phase III protocols, the Coordinating Center with NHLBI
and the Steering Committee will have the responsibility to identify qualified
and interested investigators at non-Core centers who wish to enroll patients
on these protocols. Funding will be provided to these investigators on a per
patient basis. Arrangements for data collection and reimbursement of trial-
related data collection costs at non-Core centers will be the responsibility
of the Data Coordinating Center. The Data Coordinating Center will also be
responsible for obtaining biologic reagents, organizing correlative laboratory
studies, arranging for storage of patient samples, and procuring other
resources as required by the clinical protocols. These activities may involve
the establishment of a central laboratory and a biologic specimen repository.
A Steering Committee will be the main governing body of the Network and, at a
minimum, will be composed of the principal investigators of the Core Clinical
Centers and the Data Coordinating Center and the NHLBI Project Scientist. The
Steering Committee Chairperson, who will be someone other than an NHLBI staff
member and may be someone other than a principal investigator, will be
selected by NHLBI. The Core Clinical Centers, the Data Coordinating Center,
and the NHLBI each will have one vote. The Chairperson will vote in the case
of ties. The Steering Committee may meet as often as four times in the first
12 months of the Network, and two to four times per year thereafter. All
major scientific decisions will be determined by majority vote of the Steering
Committee.
The Steering Committee will have primary responsibility for the general
organization of the Network, finalizing common clinical protocols,
facilitating the conduct and monitoring of the studies, and reporting study
results. Topics for the protocols will be proposed and prioritized by the
Steering Committee with input from the wider transfusion medicine and
hemostasis community. For each protocol, one investigator (or small group)
will take the lead responsibility for drafting the protocol along with the
Data Coordinating Center, although the Steering Committee will provide input
and will be responsible for assuring development of a common protocol to be
implemented by other Clinical Centers.
Subcommittees of the Steering Committee will be established as necessary, for
example, it is envisioned that a Publications and Presentations Committee will
prioritize, facilitate and supervise preparation and review of manuscripts
prior to submission for publication. Data collections will be monitored in a
manner consistent with Guidelines for Data Quality Assurance in Clinical
trials and Observational Studies
http://www.nhlbi.nih.gov/funding/policies/dataqual.htm.
An independent Protocol Review Committee, established by NHLBI with input from
the Steering Committee, will provide peer review for each protocol. A Data
and Safety Monitoring Board (DSMB), similarly established, will monitor
patient safety and review performance of each study approximately semi-
annually. As a part of its monitoring responsibility, the DSMB will submit
recommendations to NHLBI regarding the continuation of each study and prepare
a report for principal investigators to provide to their institutional review
boards (IRBs.)
It is required that each protocol will be conducted in at least four or more
of the Core Clinical Centers. As specific protocols are developed, support
will depend on the availability of funds and will be provided on a per patient
basis. All the Core Clinical Centers must be willing to pursue this funding
arrangement for each new protocol conducted. Clinical protocols must be
approved by local IRBs and the Protocol Review Committee before initiation.
The exact number of protocols supported in the 5 year program will depend on
the nature and extent of the investigations proposed by the Steering Committee
and the availability of funds. Both short and long term projects (not to
exceed the funding period of the RFA)should be considered. All projects must
be completed within the five year duration of this research program.
Research Scope
The treatment of patients with hemostatic disorders that are congenital in
origin (eg, hemophilia A), immune mediated (eg, idiopathic thrombocyopenic
purpura (ITP) or thrombotic thrombocytopenic purpura (TTP)) or due to
coagulopathies resulting from chemotherapy, surgery, or trauma all require
collaboration between physicians who are specialized in transfusion medicine
and those with specialized knowledge of hemostasis. For some of the
relatively rare disorders, new treatments are available, they may be extremely
costly and may not have been compared to other less costly but effective
agents. Without systematic studies, the best choices of treatment for specific
patients cannot be made. For example, patients with ITP may receive one or
more courses of glucocorticoids which may eventually be followed by
splenectomy if necessary. However, for patients who have chronic ITP, multiple
immune-based treatment options have been described, yet none has been studied
in large numbers of patients in a systematic fashion. For patients with TTP,
the recurrence rate after successful plasma exchange is higher than 20 per
cent, some small studies suggest that splenectomy may prevent recurrence, yet
large trials have not been performed in this relatively uncommon but
potentially lethal disorder. The recogniton that acquired TTP is an immune-
based disorder suggests that newer strategies can also be tested as adjunctive
therapy to plasma exchange.
A new hemostatic agent, recombinant factor VIIa, has shown efficacy in
multiple clinical settings other than for those patients with antibodies to
factor VIII or factor IX. However, its extreme cost makes knowledge of the
appropriate use imperative for cost-effective medical practice. This can be
obtained only through collaborative studies in well-defined patient groups.
Another major challenge in hemostasis concerns the need for providing support
for patients with potential or actual bleeding disorders due to severe
thrombocytopenia. Platelet concentrates, which can only be stored for five
days, are frequently in short supply in many hospitals with active cancer
centers. Thus, investigation of platelet substitutes, platelets with prolonged
shelf-lives, and the potential role for thrombopoietin in promoting platelet
production is an important aspect of research in hemostasis.
Patients who are thrombocytopenic because of chemotherapy also may have
neutropenia and would be ideal candidates for studies of the role of
granulocyte infusions in preventing or improving treatment of infections in
this clinical setting.
The objective of this RFA is to establish a Transfusion Medicine/Hemostasis
Clinical Research Network that will accelerate research in the appropriate use
of blood products and novel growth factors and in the treatment of hemostatic
disorders, such as ITP and TTP. The network will standardize approaches to
existing diagnoses and treatments, and evaluate new ones. The emphasis will
be on clinical trials with a goal toward facilitating optimal therapy.
Therapeutic trials may involve investigational drugs or blood products,
including those already approved but not currently used, and those currently
used. The network will emphasize the strength of the close collaborations
between experts in transfusion medicine and those in hemostasis (and
hematology) to potentially explore the role for other blood derived products
such as granulocytes. All projects must be completed within the 5 year
duration of this research program. Some examples of research questions
appropriate for this RFA include, but are not limited to, the following:
o Trials of novel immunomodulatory strategies versus standard of care in the
treatment of patients with chronic ITP and for those with TTP.
o Trial of newer immunomodulatory strategies versus standard of care for
treatment of individuals with hemophilia (and also those without hemophilia)
who develop antibodies to factor VIII.
o Trial of recombinant factor VIIa at different doses versus standard of care
in providing hemostasis to patients with coagulopathies due to liver failure
or disseminated intravascular coagulation who are at high risk for bleeding or
who are actively bleeding.
o Trials evaluating new factor concentrates and hemostatic agents in treating
bleeding associated with congenital and acquired bleeding disorders.
o Trials comparing platelet substitutes as well as those stored under
different conditions with standard platelet infusions in reducing bleeding in
thrombocytopenic patients. In addition, depending on availability of the
product, trials can be established to determine the safety and efficacy of
recombinant thrombopoietin in stimulating platelet production in platelet
donors and in patients with thrombocytopenia.
o Trials of granulocyte transfusions versus standard of care in reducing
morbidity and mortality in patients with granulocytopenia.
These are examples only. Applicants are not limited to the subjects mentioned
above and are encouraged to submit other topics pertinent to the objectives of
the RFA.
Research Plan
Each Core Clinical Center must propose a research plan that includes two
protocols developed by the applicant that could be used as a model in the
network environment. The protocols should demonstrate knowledge in the areas
of transfusion medicine/hemostasis. Each protocol should require sufficient
subjects to require use of the network with multi-center participation.
Applicants should indicate knowledge of the numbers of the patients required
for each of the studies based on sample size calculations. One protocol must
be short-term (two years or less) and the other long-term (more than two years
but completed within the overall five year time frame). A consortium
arrangement involving a multi center protocol may be proposed as a third
protocol, however, it can only be included if two primary protocols are
proposed. The two primary protocols must have been developed by the
applicant, and a time-line should be included for all protocols. Inclusion of
a registry to monitor outcomes within a protocol is acceptable, provided that
the registry falls within the time constraints of the RFA. Applicants must not
provide more than three protocols. Each protocol may focus on a hemostasis or
transfusion medicine question, or may involve both research areas. Priority
will be given to randomized studies and to those that focus on significant
clinical issues that are likely to have a high impact on clinical medicine.
In the event that randomization is not feasible, innovative alternatives to
randomization will be considered. The protocols should demonstrate knowledge
about transfusion medicine and/or hemostasis, ask clinically relevant
questions, and require sufficient subjects to necessitate the use of a multi-
center network. Applicants should provide preliminary results that justify
the proposed end points and sample size.
The research plan should follow the instructions in the PHS 398 application
form which can be found at http://grants.nih.gov/grants/forms.htm. For the
protocol, include a description of the rationale, research aims, outcome
measures, and study design, a description of the patient populations with an
estimate of the expected distribution of minority and female patients, ages,
and assurances of the applicant"s access to the patient populations. Identify
any competing protocols and provide an algorithm to explain patient allocation
among them.
Core Clinical Center applicants should indicate for each protocol how many
patients are available in the applicant=s center and how many will be required
from the network. The center=s estimate of eligible patients should be based
on the actual number of patients with that particular clinical problem
treated in the year 2000. For studies of hemostasis disorders, applicants
should document that they have access to at least 20 patients per year, for
transfusion medicine research studies, applicants should document that they
have access to at least 200 patients who receive cellular and/or plasma
components per year. Transfusion medicine research applicants should provide
a summary of the number of blood and/or plasma components collected and
infused in patients at their institution during the year 2000.
It is the intent of this Network that multiple trials will be conducted during
the five year project period. It is anticipated that in the initial year, two
trials will be selected from the studies proposed by the successful
applicants. However, a decision to fund a particular Core Clinical Center
will not commit the Network to develop that center=s clinical protocol.
Nevertheless, awardees must agree to actively enroll patients in at least two
Network trials per year. Applicants should plan that after the first year at
least four trials will begin enrolling patients each year. All applicants
should propose a strategy to streamline protocol development and acceptance
among centers, given this ambitious pace for initiating trials. Initiation of
trials in future years will depend on satisfactory progress in previous
trials.
Data Coordinating Center applicants should propose one clinical protocol from
the perspective of study design, implementation, coordination and data
analysis. Include a plan for recruiting patients from non-Core centers for
studies that warrant it. Indicate appropriate objective measures of primary
and secondary outcome. Describe methods to standardize reporting of platelet
refractoriness and platelet yield for studies of platelet transfusions,
propose a registry to track serious adverse events, show plans to undertake
quality of life studies, and present an innovative approach for performing
randomized studies at an early stage of investigation. Such approaches
include, but are not limited to, use of internal pilot studies, methods for
early stopping for futility or benefit, methods of adaptive trial redesign and
other recently developed methods which will increase the efficiency of trial
conduct. Development of new methods is encouraged.
The entire application for Core Clinical Centers including protocols should
not exceed the Form 398 Research Plan instructions of 25 pages. The Data
Coordinating Center application may include an additional 5 pages to
accommodate the clinical protocol proposal.
SPECIAL REQUIREMENTS
Terms and Conditions of Award
The cooperative agreement is an award instrument establishing an "assistance"
relationship (in contrast to an "acquisition" relationship) between NHLBI and
a recipient, in which substantial NHLBI scientific and/or programmatic
involvement with the recipient is anticipated during performance of the
activity. The NHLBI purpose is to support and/or stimulate the recipient=s
activity by involvement in and otherwise facilitating the activity in a
"partner" role, but avoiding a dominant role, direction, or prime
responsibility. The terms and conditions below elaborate on these actions and
responsibilities, and the awardee agrees to these collaborative actions with
the NHLBI Project Scientist toward achieving the project objectives. It is
anticipated that these terms and conditions will enhance the relationship
between the NHLBI staff and the Principal Investigator(s), and will facilitate
the successful conduct and completion of the study. These agreements will be
in addition to, and not in lieu of, the relevant NIH procedures for grants
administration. The terms will be as follows:
1. The awardee(s) will have lead responsibilities in all aspects of the
study, including any modification of study design, conduct of the study,
quality control, data analysis and interpretation, preparation of
publications, and collaboration with other investigators, unless otherwise
provided for in these terms or by action of the Steering Committee.
2. The NHLBI Project Scientist will serve on the Steering Committee, he/she
or another NHLBI scientist may serve on other study committees, when
appropriate. The NHLBI Project Scientist (and the other cited NHLBI
scientists) may work with awardees on issues coming before the Steering
Committee and, as appropriate, other committees, e.g.: recruitment,
intervention, follow-up, quality control, adherence to protocol, assessment of
problems affecting the study and potential changes in the protocol, interim
data and safety monitoring, final data analysis and interpretation,
preparation of publications, and development of solutions to major problems
such as insufficient participant enrollment.
3. Awardee(s) agree to the governance of the study through a Steering
Committee. Steering Committee voting membership shall consist of the principal
investigators (i.e., cooperative agreement awardees), the NHLBI Project
Scientist, and the Study Chair. Meetings of the Steering Committee will
ordinarily be held by telephone conference call or in the metropolitan
Washington Area.
4. A Data and Safety Monitoring Board will be appointed by the Director,
NHLBI to provide overall monitoring of interim data and safety issues, the
Steering Committee will nominate members for this Board. Meetings of the Data
and Safety Monitoring Board will ordinarily be held in Bethesda. The NHLBI
Project Scientist shall serve as Executive Secretary to the Board. An
Independent Protocol Review Committee, established by the NHLBI, will provide
peer review for each protocol.
5. Awardees will retain custody of and have primary rights to their data
developed under these awards, subject to Government rights of access
consistent with current HHS, PHS, and NIH policies. The collaborative protocol
and governance policies will call for the continued submission of data
centrally to the coordinating center for a collaborative database, the
submittal of copies of the collaborative datasets to each principal
investigator upon completion of the study, procedures for data analysis,
reporting and publication, and procedures to protect and ensure the privacy of
medical and genetic data and records of individuals. The NHLBI Project
Scientist, on behalf of the NHLBI, will have the same access, privileges and
responsibilities regarding the collaborative data as the other members of the
Steering Committee (i.e., cooperative agreement awardees).
6. Support or other involvement of industry or any other third party in the
study -- e.g., participation by the third party, involvement of study
resources or citing the name of the study or NHLBI support, or special access
to study results, data, findings or resources -- may be advantageous and
appropriate. However, except for licensing of patents or copyrights, support
or involvement of any third party will occur only following notification of
and concurrence by NHLBI.
7. Awardees are encouraged to publish and to publicly release and disseminate
results, data and other products of the study, concordant with the study
protocol and governance, and the approved plan for making data and materials
available to the scientific community and to the NHLBI. However, during or
within three years beyond the end date of the project period of NHLBI support,
unpublished data, unpublished results, data sets not previously released, or
other study materials or products are to be made available to any third party
only with the approval of the Steering Committee and in accordance with
paragraph 6.
8. The NHLBI reserves the right to terminate or curtail the study (or an
individual award) in the event of (a) failure to develop or implement a
mutually agreeable collaborative protocol, (b) substantial shortfall in
participant recruitment, follow-up, data reporting, quality control, or other
major breach of the protocol, (c) substantive changes in the agreed-upon
protocol with which NHLBI cannot concur, (d) reaching a major study endpoint
substantially before schedule with persuasive statistical significance, or (e)
human subject ethical issues that may dictate a premature termination.
9. Any disagreement that may arise in scientific/programmatic matters (within
the scope of the award), between award recipients and the NHLBI may be brought
to arbitration. An arbitration panel will be composed of three members--one
selected by the Program Steering Committee (with the NHLBI member not voting)
or by the individual awardee in the event of an individual disagreement, a
second member selected by NHLBI, and the third member selected by the two
prior members. This special arbitration procedure in no way affects the
awardee"s right to appeal an adverse action that is otherwise appealable in
accordance with the PHS regulations at 42 CFR part 50, Subpart D and HHS
regulation at 45 CFR part 16, or the rights of NHLBI under applicable
statutes, regulations and terms of the award.
10. These special terms of award are in addition to and not in lieu of
otherwise applicable OMB administrative guidelines, HHS Grant Administration
Regulations at 45 CFR part 74, and other HHS, PHS, and NIH grant
administration policy statements.
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS
It is the policy of the NIH that women and members of minority groups and
their sub-populations must be included in all NIH-supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification are provided indicating that inclusion
is inappropriate with respect to the health of the subjects or the purpose of
the research. This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).
All investigators proposing research involving human subjects should read the
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research," published in the NIH Guide for Grants and Contracts on
August 2, 2000
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html),
a complete copy of the updated Guidelines are available at
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The
revisions relate to NIH defined Phase III clinical trials and require: a) all
applications or proposals and/or protocols to provide a description of plans
to conduct analyses, as appropriate, to address differences by sex/gender
and/or racial/ethnic groups, including subgroups if applicable, and b) all
investigators to report accrual, and to conduct and report analyses, as
appropriate, by sex/gender and/or racial/ethnic group differences.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS
It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them.
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.
All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines" on the Inclusion of Children as Participants in
Research Involving Human Subjects that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html
Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES. Program staff may also provide additional relevant
information concerning the policy.
REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS
NIH policy requires education on the protection of human subject participants
for all investigators submitting NIH proposals for research involving human
subjects. This policy announcement is found in the NIH Guide for Grants and
Contracts Announcement dated June 5, 2000, at the following website:
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
URLS IN NIH GRANT APPLICATIONS OR APPENDICES
All applications and proposals for NIH funding must be self-contained within
specified page limitations. Unless otherwise specified in an NIH
solicitation, internet addresses (URLs) should not be used to provide
information necessary to the review because reviewers are under no obligation
to view the Internet sites. Reviewers are cautioned that their anonymity may
be compromised when they directly access an Internet site.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT
The Office of Management and Budget (OMB) Circular A-110 has been revised to
provide public access to research data through the Freedom of Information Act
(FOIA) under some circumstances. Data that are (1) first produced in a
project that is supported in whole or in part with Federal funds and (2) cited
publicly and officially by a Federal agency in support of an action that has
the force and effect of law (i.e., a regulation) may be accessed through FOIA.
It is important for applicants to understand the basic scope of this
amendment. NIH has provided guidance at:
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm
Applicants may wish to place data collected under this RFA in a public
archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application should
include a description of the archiving plan in the study design and include
information about this in the budget justification section of the application.
In addition, applicants should think about how to structure informed consent
statements and other human subjects procedures given the potential for wider
use of data collected under this award.
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent that includes a
descriptive title of the proposed research, the name, address, and telephone
number of the Principal Investigator, the identities of other key personnel
and participating institutions, and the number and title of the RFA in
response to which the application may be submitted. Although a letter of
intent is not required, is not binding, and does not enter into the review of
a subsequent application, the information that it contains allows NHLBI staff
to estimate the potential review workload and plan the review.
The letter of intent is to be sent by fax or mail to Dr. Deborah Beebe at the
address listed under INQUIRIES by January 25, 2002.
APPLICATION PROCEDURES
The PHS 398 research grant application instructions and forms (rev. 5/2001) at
http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in
applying for these grants. This version of the PHS 398 is available in an
interactive, searchable PDF format. Beginning January 10, 2002, the NIH will
return applications that are not submitted on the 5/2001 version. For further
assistance contact GrantsInfo, Telephone 301/435-0714, Email:
GrantsInfo@nih.gov.
SPECIFIC INSTRUCTIONS
Material to Include in Core Clinical Center Applications:
To promote development of a collaborative program among the award recipients,
the issues discussed below need to be addressed in each application for a Core
Clinical Center and will be considered during the review of the application.
This material is in addition to the submission of a research plan, as
described in the section entitled Research Scope and should be included within
the 25 page limit.
Patient Access. Core Clinical Center applicants must document that they have
access to at least 20 patients per year undergoing treatment for hemostasis
disorders that would be studied in the protocols, or 200 patients per year who
receive cellular and/or plasma transfusion products. Applicants should
provide documentation of the numbers of patients treated in the year 2000.
Transfusion medicine applicants should also provide a summary of the number of
blood and plasma components collected and infused in patients at their
institution during the year 2000. It is not anticipated that all patients
will be enrolled in research protocols at any one time. It is possible that
an individual patient may be enrolled in more than one study. Centers should
estimate the number of patients that will be eligible for Network protocols,
provide information on competing protocols, and present a strategy for
allocating patients between them.
Study population. The application should include a description of the pool of
potential study participants--the age range, ethnic/racial distribution, and
estimated distribution of patients with the disorders that would be studied in
the Network protocols. The Network application should include racial/ethnic
minorities, children and women in ratios that at least approximate their
likelihood of having the diseases being studied and provide sufficient
clinical events to perform subgroup analyses.
Plans to release data. Applicants should provide a plan for the dissemination
of results to study patients. Awardees will retain custody of and have primary
rights to the data developed under these awards, subject to Government rights
of access consistent with current federal policies. The collaborative
protocol and governance policies will require submission of data to the
coordinating center for a collaborative database, specify procedures for data
analysis, reporting and publication, and include procedures to protect and
ensure the privacy of medical and genetic data and records of individuals.
Copies of the collaborative data sets will be provided to each principal
investigator after publication of study results. Each Awardee will comply
with the approved data release plan.
Awardees are encouraged to publish and to publicly release and disseminate
results, data and other products of the study, concordant with the study
protocol and governance and the approved plan for making data and materials
available to the scientific community, NHLBI, and the public. No later than
three years beyond the end date of the project period, unpublished data, data
sets not previously released, or other study materials or products are to be
made available to any interested party at no charge other than the costs of
reproduction and distribution. At the end of the project, the Data
Coordinating Center is expected to electronically place all study protocols
and procedure manuals in the public domain and/or make them available to other
interested parties at no charge other than the costs of reproduction and
distribution, according to the approved plan for making data and materials
available to the scientific community.
Willingness and ability to participate in the Network. Applicants should
provide a history of their participation in collaborative research and state
their general support of collaborative research and interaction with other
Core Clinical Centers, the Data Coordinating Center, and NHLBI through the
network. Centers must be willing to initiate randomized studies of promising
therapies as soon as they are warranted. Centers must discuss their
willingness to participate in Network trials even if the protocols they
proposed are not selected for implementation. Applicants should discuss their
willingness to accept per patient reimbursement (capitation) for each protocol
as decided by the Steering Committee and NHLBI staff.
Budget and Related Issues for Core Clinical Centers
Core Clinical Center applicants should consider the following issues regarding
budgets. The underlying concept of the Network is that a core effort is
essential to maintain the infrastructure required to perform prospective
multi-institution clinical trials. Based on this approach, it is estimated
that the Core Clinical Centers will require a minimum level of effort to
sustain the organizational aspects of the Network.
Patient-related costs. In addition to the core budget, each Core Clinical
Center will be provided funds for implementation of protocols on a per
patient-enrolled basis. Funds for per patient costs will be restricted for
this purpose. Costs for a required part of the patient=s treatment may not be
requested from the grant. Costs for tests and treatment not part of the usual
procedure may be requested. Laboratory tests specifically required by
clinical protocols will be included as a part of the per patient costs of each
Core Clinical Center. (Costs for tests that are a routine part of patients=
clinical care should not be included and may not be paid from grant funds.)
Allowable total costs for each clinical center (core costs, costs per patient
to conduct the protocols, and facility and administrative costs) will be
limited to $300,000 a year.
The precise number of protocols conducted over the 5 years will be determined
by the Network Steering Committee and will depend on availability of funds.
Each clinical center must participate in at least two protocols per year. The
initiation of two protocols is expected in the first year, and at least four
new trials are expected to begin enrolling patients in future years.
Initiation of trials in future years will depend on satisfactory progress in
previous trials.
Applicants for the Core Clinical Centers are requested to present the
following information:
For each year, the Clinical Centers should include the core budget costs and
patient care costs. The core budget which is limited to $150,000 total costs
is expected to cover a minimum 10% effort for the principal investigator, and
the percent efforts for other key personnel (nurse, technician, clinic
coordinator), and travel costs for two people to attend 4 Network meetings per
year in Bethesda, MD. Total costs for the core budget may be escalated at
three percent for future years. Actual patient care costs will be determined
by the specific protocols implemented at each center. For application
purposes, $150,000 (total costs) should be entered on the patient care cost
line on the budget page without escalation. This amount will be restricted
for this purpose. Funds released will reflect protocol-specific costs as
protocols are implemented.
For the purpose of the review, centers should provide separate budgets for
each clinical protocol they propose. Applicants must not provide more than
two protocols. Each protocol may focus on a hemostasis or transfusion
medicine question, or both research areas. The clinical protocol budgets
should be developed on a cost per patient basis and include all direct and any
applicable facilities and administrative costs. Costs of recruiting and
following patients, costs for drugs or procedures, and costs for laboratory
tests should be part of the per patient cost of conducting a protocol.
Applications should identify the potential source(s) and cost for any drugs or
procedures that are being considered for clinical protocols. The yearly budget
for each protocol should include the number of patients available for the
proposed protocol at the applicant=s center.
Investigators should prepare budgets only for their own center to conduct the
proposed trial, and not for the entire Network. However, the budget should
state the total number of patients required from the entire network to
complete each proposed trial.
Continuation and level of funding for each Core Clinical Center will be based
on actual recruitment and overall performance. Awards will be subject to
administrative review annually. The entire Network will be administratively
reviewed after approximately three years.
Material to Include in Data Coordinating Center Applications:
To promote development of a collaborative program among the award recipients,
the issues discussed below need to be addressed in each application for a Data
Coordinating Center and will be considered during the review of the
application. This material is in addition to the submission of a research
plan, as described in the section entitled Research Scope and should be
included within the 25 page limit. The Data Coordinating Center application
may include an additional 5 pages to accommodate the clinical protocol
proposal as noted above.
Qualifications and experience. Applicants for the Data Coordinating Center
must demonstrate knowledge in the area of transfusion medicine/hemostasis and
experience in coordinating multi-center clinical trials in all phases:
protocol and manual of operations development, staff training in study
procedures, data form development, patient recruitment strategies, data
collection and management, quality assurance, data analysis, distributed data
entry, electronic communications including web site development and
management, administrative management and coordination. The experience of key
personnel should be described.
Study design and management. Data Coordinating Center applicants should
discuss various aspects of study design that would be important in developing
clinical protocols, for example: eligibility criteria, baseline and outcome
measures, methods of randomization, important considerations for sample size
and power calculations, methods and frequency of data collection and entry,
monitoring accuracy of data collection including at least yearly site visits,
quality control procedures including training and certification for multiple
protocols, some of which may occur simultaneously, managing, labeling and
handling of patient samples (see below), and plans for statistical analysis.
Applicants should provide a time line for protocol development and a strategy
for reducing the time required to initiate patient enrollment in new studies.
Experience in and plans for development and use of novel statistical study
designs should be described. Applicants should describe their familiarity
with transfusion medicine and/or hemostasis. Plans for coordinating the Data
Safety Monitoring Board and the Protocol Review Committee should be included.
Applicants should provide a plan for the dissemination of results.
Patient enrollment at Core Clinical Centers. Propose a method for screening
eligible patients at Core Centers and identifying causes of non-enrollment.
Describe previous experience with strategies to improve accrual in randomized
clinical studies.
Patient enrollment at outside centers. In order to produce the fastest
possible accrual to phase III, studies it is desirable that studies be
accessible to as many patients as possible. The applicant should include a
plan to identify interested non-Core medical centers, evaluate their ability
to enroll patients to a specific protocol, collect data from these centers,
conduct onsite data audits at these centers, and provide per capita
reimbursement for enrollment to these centers.
Patient samples. The applicant should delineate how laboratory specimens
required for specific studies will be handled and be prepared to submit plans
for identifying a central laboratory(ies), establishing a specimen repository,
or obtaining other services as needed for specific protocols. The costs of
obtaining protocol-specific tests or services will be budgeted as a part of
the per patient costs of each Clinical Center. (Costs for tests that are a
routine part of the patients= clinical care should not be included and may not
be paid from grant funds.) The costs of specimen shipment as well as
laboratory data acquisition and management will be a part of the budget of the
Data Coordinating Center. Estimated shipping and handling costs per year for
specimens should be included in the budget of the Data Coordinating Center.
Central source of drugs and investigational agents. The applicant should
describe in general terms plans to obtain needed drugs, biologic reagents, or
devices and describe their experience with studies of investigational agents.
Budget and Related Issues for Data Coordinating Center Applicants:
Applicants for the Data Coordinating Center should prepare budgets for five 12
month periods that roughly correspond with the standard coordinating center
responsibilities outlined in other sections of this RFA. For budget purposes,
Data Coordinating Center applicants should assume that in the first year, all
administrative aspects of the Network will be organized and two protocols will
be developed and started. For subsequent years, applicants should assume that
at least four new protocols will be initiated each year.
Data Coordinating Center applicants should include costs for managing the DSMB
and the Protocol Review Committee including the cost of three meetings per
year in Bethesda. In addition, funds for reimbursing non-Core centers for
patient accrual as well as appropriate oversight should be included. The Data
Coordinating Center should budget $50,000 in total costs for expenses related
to support for the chair of the Steering Committee. It is estimated that in
addition to the standard data coordinating center responsibilities, the per
patient reimbursement, laboratory tests and services, and biologic reagents
will cost an additional $280,000 total per year.
The award will be subject to administrative review annually. There will be an
administrative review by NHLBI after approximately three years to determine if
the network and each of its components has been performing as envisioned in
terms of patient recruitment and implementation of protocols of importance to
the field. It is expected that all protocols will be performed in a manner
consistent with United States Food and Drug Administration guidelines.
APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED
UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW.
The RFA label available in the PHS 398 (rev. 5/2001) application form must be
affixed to the bottom of the face page of the application. Type the RFA
number on the label. Failure to use this label could result in delayed
processing of the application such that it may not reach the review committee
in time for review. In addition, the RFA title and number must be typed on
line 2 of the face page of the application form and the YES box must be
marked. The RFA label is also available at:
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
Submit a signed, typewritten original of the application, including the
Checklist, and three signed, photocopies, in one package to:
CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)
At the time of submission, two additional copies of the application as well as
all five collated sets of Appendix material must be sent to Dr. Deborah Beebe
at the address listed under Inquiries. Applications must be received by the
application receipt date listed in the heading of this RFA. If an application
is received after that date, it will be returned to the applicant without
review.
The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application. The
CSR also will not accept any application that is essentially the same as one
already reviewed. This does not preclude the submission of substantial
revisions of applications already reviewed, but such applications must include
an introduction addressing the previous critique.
Principal investigators should not sent supplementary material without first
contacting the Scientific Review Administrator (SRA). The SRA will be
identified in the letter sent to you indicating that your application has been
received. If you have not received such a letter within three weeks after
submitting the application, contact Dr. Deborah Beebe at the address listed
under Inquiries.
REVIEW CONSIDERATIONS
Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NHLBI. Incomplete and/or non-responsive applications
will be returned to the applicant without further consideration.
Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group convened by
the NHLBI in accordance with the review criteria stated below. As part of the
initial merit review, all applications will receive a written critique and
undergo a process in which only those applications deemed to have the highest
scientific merit, generally the top half of the applications under review,
will be discussed, assigned a priority score, and receive a second level
review by the National Heart, Lung, and Blood Advisory Council.
Review Criteria for Core Clinical Center Applications
o Research plan. Appropriateness of proposed protocol(s), need for the
network to accomplish the proposed protocol, relevance and importance of the
research questions, preliminary results that justify the proposed end points
and sample size, and likelihood that accrual could be accomplished in three
years.
o Qualifications and experience. The expertise, training, and experience of
the investigators and staff in transfusion medicine/hemostasis clinical
trials, evidence of understanding of randomized, multi-center trials,
administrative abilities of the Principal Investigator, study nurse and/or
data coordinator, and the level of commitment to the program for the effective
function of the Clinical Research Network.
o Patient access and study population. The availability of at least 20
patients with disorders of hemostasis per year or a transfusion medicine
program with access to at least 200 patients receiving cellular or plasma
components per year, the number that will be eligible for Network protocols,
plans for the recruitment and retention of subjects, plans to ensure
appropriate representation by ethnic group, age, and gender, the description
of competing protocols, and the strategy for allocating patients between them.
o Willingness and ability to participate in the Network. Applicant
institution=s history of collaborative research, depth of commitment,
willingness to randomize patients, and ability to work with other Network
Centers and NHLBI.
o Institutional resources for patient care and follow-up. Adequacy of
institutional resources including personnel, space, and special laboratory
facilities.
Review Criteria for Data Coordinating Center Applications
o Research plan. Demonstrates understanding of the scientific, statistical,
logistical, and technical issues underlying multi-center studies, including
issues relating to assessment of outcomes relating to use of novel blood
products and treatment of patients with bleeding disorders, and demonstrates
leadership in study design and statistics, data acquisition and management,
data quality control, data analysis, handling and quality control of
laboratory specimens, and network coordination.
o Qualifications and experience. The expertise, training, and experience of
the investigators and staff, including the administrative abilities of the
Principal Investigator, co-investigator, and the time they plan to devote to
the program for the effective coordination of the Network.
o Study management. The administrative, supervisory, and collaborative
arrangements for achieving the goals of the program, including willingness to
cooperate with the participating Clinical Centers and the NHLBI. This
includes the ability to assist Core Clinical Centers with recruitment
problems, and identify and subcontract with non-Core clinical centers to meet
accrual goals.
o Willingness and ability to participate in the Network. Applicant
institution=s history of collaborative research, depth of commitment, and
ability to work with other Network Centers and the NHLBI.
o Environment. Facilities, equipment, and organizational structure to
effectively coordinate Clinical Research Network activities and assist
Clinical Centers in implementing the Clinical Research Network protocols,
providing for specialized laboratory testing, and collecting data. This
includes but is not limited to development of repositories, conduct of lab
tests and studies, and obtaining study drugs or investigational agents.
In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:
o The adequacy of plans to include both genders, minorities and their
subgroups, and children as appropriate for the scientific goals of the
research. Plans for the recruitment and retention of subjects will also be
evaluated.
o The reasonableness of the proposed budget and duration in relation to the
proposed research.
o The adequacy of the proposed protection for humans, animals or the
environment, to the extent they may be adversely affected by the project
proposed in the application.
Schedule
Letter of Intent Receipt Date: January 25, 2002
Application Receipt Date: February 22, 2002
Peer Review Date: June/July 2002
Council Review: September 2002
Earliest Anticipated Start Date: September 30, 2002
AWARD CRITERIA
Award criteria that will be used to make award decisions include:
o scientific merit (as determined by peer review)
o availability of funds
o programmatic priorities.
INQUIRIES
Inquiries concerning this RFA are encouraged. The opportunity to clarify any
issues or answer questions from potential applicants is welcome.
Direct inquiries regarding programmatic issues to:
Dr. Liana Harvath
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10170, MSC 7950
Bethesda, Maryland 20892-7950
Telephone: (301) 435-0065
FAX: (301) 480-0868
E-mail: harvathl@nhlbi.nih.gov
Send letter of intent, copies of the application and direct inquiries
regarding review matters to:
Dr. Deborah Beebe
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 7178, MSC 7924
Bethesda, Maryland 20892-7924
Telephone: (301) 435-0270
FAX: (301) 480-3541
E-mail: beebed@nhlbi.nih.gov
Direct inquiries regarding fiscal matters to:
Suzanne White
Grants Operations Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 7174, MSC 7926
Bethesda, MD 20892-7926
Telephone: (301) 435-0166
FAX: (301) 480-3310
Email: sw52h@nih.gov
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance No.
93.839. Awards are made under authorization of Sections 301 and 405 of the
Public Health Service Act as amended (42 USC 241 and 284) and administered
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts
74 and 92. This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency review.
The PHS strongly encourages all grant recipients to provide a smoke-free
workplace and promote the non-use of all tobacco products. In addition,
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care, or early childhood
development services are provided to children. This is consistent with the
PHS mission to protect and advance the physical and mental health of the
American people.